The overall objective of this revised competing continuation is to advance our understanding of the role of the inflammatory response in the development of type 2 diabetes over the course of 3 to 9 years of follow-up in a population-based cohort of middle-aged African-American and white men and women. We propose to continue investigation of a case-cohort sample from the NHLBI-supported Atherosclerosis Risk in Communities (ARIC) Study, capturing the experience of 10,275 individuals, among whom 1155 incident cases of diabetes have been detected. We will build on the design developed in the initial grant period, in which we have selected, in a very cost-efficient manner, a stratified random sample of 581 incident diabetes cases and a cohort stratified random sample of 693 individuals. Using plasma collected and stored at the baseline (pre-diabetic) exam, we will investigate potential sources (advanced glycation end product proteins, oxidative stress) and modulators (smoking) of inflammation; additional components of the inflammatory response (macrophage inhibitory factor, macrophage chemo attractant protein-1 and dipeptidyl peptidase-IV); and modulators of carbohydrate metabolism potentially altered by the inflammatory response (pancreatic beta-cell function, incretins, growth factors, ghrelin, endothelial cell function). This study will allow definition of the significance, at a clinical and population level, of specific aspects of this emerging focus of research on inflammation and the pathogenesis of type 2 diabetes. The availability of a rich database of analytes assembled during the initial grant period, including cytokines, acute phase reactants, liver function tests and adiponectin, the large number of incident cases, and the significant representation of African-American subjects makes this a unique and powerful study population to evaluate new and emerging hypotheses.